title: Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target.
abstract: Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
authors.affiliation: Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, London WC1N 1AX, UK.
authors.forename: Ina L
authors.initials: IL
authors.lastname: Lauinger
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Remo
authors.initials: R
authors.lastname: Perozzo
authors.forename: Christopher
authors.initials: C
authors.lastname: Stairiker
authors.forename: Alice
authors.initials: A
authors.lastname: Tarun
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Xujie
authors.initials: X
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Duc-Hung
authors.initials: DH
authors.lastname: Pham
authors.forename: Camila V
authors.initials: CV
authors.lastname: Esguerra
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Crawford
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Deniz
authors.initials: D
authors.lastname: Tasdemir
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors* / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008011:Lichens / Q000737:chemistry*; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D015800:Protozoan Proteins / Q000097:blood / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D015027:Zebrafish
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D054889:Fatty Acid Synthase, Type II